Dracunculus medinensis, or Guinea worm (GW), causes a painful and debilitating infection in people. The Guinea Worm Eradication Program (GWEP) has successfully reduced human GW cases from 3.5 million in 21 countries in 1986 to 11 in four remaining endemic countries in 2018. In 2011, an unprecedented increase of GW infections in domestic dogs was reported and incidence has increased annually to 942 in 2018. Epidemiologically, it was posited that transmission may not occur via the classical route (i.e., ingestion of water containing infected copepods), but instead, via a paratenic host. My goals included 1) review Dracunculus species in wildlife and use these data to inform experimental transmission trials, 2) explore novel transmission routes under laboratory conditions, 3) conduct field-based surveillance of potential paratenic hosts in Chad, and 4) investigate the ecology of the North American Guinea worm, D. insignis, in wildlife and domestic animals in the United States. I showed that D. medinensis and D. insignis can experimentally infect several amphibian species, amphibians serve as paratenic hosts and natural D. medinensis infections were found in three frog species in Chad. Although fish did not become infected (as paratenic hosts), fish were able to serve as transport hosts. These data illustrate novel transmission routes with the latter causing great concern as fish are a heavily relied upon in Chad as a food source. Also, villagers feed their cats and dogs fish entrails; our data suggest this could lead to infection. Our U.S.-based studies documented numerous dog and cat infections and that raccoons (Procyon lotor) and opossums (Didelphus virginiana) were common wildlife hosts. The high prevalence of infection in opossums was previously unreported. Based on partial cytochrome c oxidase gene sequences, little diversity was noted among worms from dogs and wildlife and no geographic or host-associations were noted. We also detected D. insignis larvae in musculature of frogs, further confirming that paratenic hosts may be playing a role in transmission of Dracunculus. Collectively, these data have filled several knowledge gaps in the Dracunculus life-cycle, resulting in the development of new interventions to assist the GWEP in endemic countries.